Magnetically tunable negative permeability metamaterial composed by split ring resonators and ferrite rods.
We experimentally demonstrate a tunable negative permeability metamaterial (NPM) at microwave frequencies by introducing yttrium iron garnet (YIG) rods into a periodic array of split ring resonators (SRRs). Different from those tuned by controlling the capacitance of equivalent LC circuit of SRR, this metamaterial is based on a mechanism of magnetically tuning the inductance via the active ambient effective permeability. For magnetic fields from 0 to 2000 Oe and from 3200 to 6000 Oe, the resonance frequencies of the metamaterial can blueshift about 350 MHz and redshift about 315 MHz, respectively. Both shifts are completely continuous and reversible. Correspondingly, the tunable negative permeabilities are widened by about 360 MHz and 200 MHz compared to that without YIG rods.


A systematic review of lifestyle patterns and their association with adiposity in children aged 5-12 years.
Diet, physical activity, sedentary behaviour and sleep are typically examined independently with childhood adiposity; however, their combined influence remains uncertain. This review aims to systematically summarize evidence on the clustering of these behaviours through lifestyle patterns and evaluate associations with adiposity in children aged 5-12 years. Search strategies were run in six databases. Twenty-eight papers met the inclusion criteria, six of which included all four behaviours. A range of lifestyle patterns were identified (healthy, unhealthy and mixed). Mixed patterns were most frequently reported. Unhealthy patterns comprising low physical activity and high sedentary behaviour were also frequently observed. Mixed patterns comprising healthy diets, low physical activity and high sedentary behaviour were more commonly seen in girls, whereas boys were more physically active, similarly sedentary and had unhealthier diets. Children from lower socio-economic backgrounds tended to more frequently display unhealthy patterns. Unhealthy lifestyle patterns were more often associated with adiposity risk than healthy and mixed patterns. With few studies including all four behaviours, it is difficult to establish a clear picture of their interplay and associations with adiposity. Nonetheless, reliance on lifestyle patterns is likely more beneficial than individual behaviours in targeting adiposity and improving understanding of how these behaviours influence health.


Infant pacifiers for reduction in risk of sudden infant death syndrome.
Sudden infant death syndrome (SIDS) has been most recently defined as the sudden unexpected death of an infant less than one year of age, with onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation, including the performance of a complete autopsy and a review of the circumstances of death and clinical history. Despite the success of several prevention campaigns, SIDS remains a leading cause of infant mortality. In 1994, a 'triple risk model' for SIDS was proposed that described SIDS as an event that results from the intersection of three factors: a vulnerable infant; a critical development period in homeostatic control (age related); and an exogenous stressor. The association between pacifier (dummy) use and reduced incidence of SIDS has been shown in epidemiological studies since the early 1990s. Pacifier use, given its low cost, might be a cost-effective intervention for SIDS prevention if it is confirmed effective in randomised controlled trials. To determine whether the use of pacifiers during sleep versus no pacifier during sleep reduces the risk of SIDS. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 2), MEDLINE via PubMed, Embase, and CINAHL to 16 March 2016. We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Published and unpublished controlled trials using random and quasi-random allocations of infants born at term and at preterm (less than 37 weeks' gestation) or with low birth weight (< 2500 g). Infants must have been randomised by one month' postmenstrual age. We planned to include studies reported only by abstracts, and cluster and cross-over randomised trials. Two review authors independently reviewed studies from searches. We found no eligible studies. We identified no randomised controlled trials examining infant pacifiers for reduction in risk of SIDS. We found no randomised control trial evidence on which to support or refute the use of pacifiers for the prevention of SIDS.


A convenient method for measuring blood ascorbate concentrations in patients receiving high-dose intravenous ascorbate.
A simple method of using fingerstick blood glucose (FSBG) monitors to estimate blood ascorbate values after high-dose intravenous (IV) ascorbate infusion is evaluated as a substitution for high-performance liquid chromatography (HPLC) measurement. In 33 participants, readings from FSBG monitors were taken before and after IV ascorbate infusions at various time points, with the postinfusion FSBG readings subtracted from the baseline glucose readings. The results of the subtractions (AAFSBG) were correlated with ascorbate concentrations detected by HPLC (AAHPLC). A linear regression was found between ascorbate concentrations detected by the fingerstick method (AAFSBG) and by HPLC (AAHPLC). The linear correlations were identical in healthy subjects, diabetic subjects, and cancer patients. Analysis of variance obtained an AAFSBG/AAHPLC ratio of 0.90, with a 90% confidence interval of (0.69, 1.20). The corrections of AAFSBG improved similarity to AAHPLC but did not significantly differ from the uncorrected values. The FSBG method can be used as an approximate estimation of high blood ascorbate concentration after IV ascorbate (>50 mg/dL, or 2.8 mM) without correction. However, this measurement is not accurate in detecting lower or baseline blood ascorbate. It is also important to highlight that in regard to glucose monitoring, FSBG readings will be erroneously elevated following IV ascorbate use and insulin should not be administered to patients based on these readings.


Temporal and geographical external validation study and extension of the Mayo Clinic prediction model to predict eGFR in the younger population of Swiss ADPKD patients.
Prediction models in autosomal dominant polycystic kidney disease (ADPKD) are useful in clinical settings to identify patients with greater risk of a rapid disease progression in whom a treatment may have more benefits than harms. Mayo Clinic investigators developed a risk prediction tool for ADPKD patients using a single kidney value. Our aim was to perform an independent geographical and temporal external validation as well as evaluate the potential for improving the predictive performance by including additional information on total kidney volume. We used data from the on-going Swiss ADPKD study from 2006 to 2016. The main analysis included a sample size of 214 patients with Typical ADPKD (Class 1). We evaluated the Mayo Clinic model performance calibration and discrimination in our external sample and assessed whether predictive performance could be improved through the addition of subsequent kidney volume measurements beyond the baseline assessment. The calibration of both versions of the Mayo Clinic prediction model using continuous Height adjusted total kidney volume (HtTKV) and using risk subclasses was good, with R2 of 78% and 70%, respectively. Accuracy was also good with 91.5% and 88.7% of the predicted within 30% of the observed, respectively. Additional information regarding kidney volume did not substantially improve the model performance. The Mayo Clinic prediction models are generalizable to other clinical settings and provide an accurate tool based on available predictors to identify patients at high risk for rapid disease progression.


Metallic nanocluster gratings generated by near-field coupling of localized surface plasmons.
Metallic nanocluster gratings composed of a 3-dimensionally periodic distribution of silver nanoparticles are successfully formed in a dielectric. A periodic arrangement of silver nanoclusters are created by holographic interference of two continuous-wave laser beams in a glass medium with embedded ~10 nm silver nanoparticles. The diffraction efficiency is much higher for the nanocluster gratings formed by TE-polarized (parallel to grating fringes) beams than those formed by TM-polarized beams. This strong polarization dependence in the formation of nanocluster gratings reveals that strong near-field coupling between localized surface plasmons excited at the metallic nanoparticles is one of the dominant mechanisms governing the rearrangement of the silver nanoparticles. The nonlinear response of metallic nanoparticles is greatly enhanced when the incident light is polarized along the lines of the silver nanoparticles.


Correlation between circulating endothelial progenitor cell function and allograft rejection in heart transplant patients.
Endothelial progenitor cells (EPCs) may contribute to rejection and cardiac allograft vasculopathy (CAV) by being intrinsically involved in the rejection process and causing neointimal hyperplasia. The mammalian target of rapamycin inhibitors (mTORi), sirolimus and everolimus, have been demonstrated to attenuate the progression of CAV and are cytotoxic to EPC. Thus, one mechanism by which mTORi may protect against CAV is by altering EPC function. Our study measured circulating EPC function and correlated this assessment with rejection episodes in heart transplant (HT) recipients. In addition, we examined the effect of mTORi on EPCs. Patients who received HT at our institution between 1995 and 2007 were included and stratified by International Society for Heart and Lung Transplantation (ISHLT) rejection grade. Group A (n = 13) consisted of patients with at least one moderate/severe rejection episode (grade > or = 2). Group B (n = 28) patients had no moderate/severe episodes (grade < 2). Patients were also independently stratified based on exposure as mTORi (n = 21) vs. non mTORi (n = 20). To assess EPC functional capacity, we counted the number of colony-forming units (CFU) of EPCs in peripheral blood samples from HT recipients. There were no significant differences in baseline characteristics between groups. The mean EPC-CFU counts/plate for group A (rejecting) were 30 +/- 6 vs.16 +/- 3 for group B (nonrejecting) (P = 0.03). The EPC-CFU counts/plate in the mTORi group (15 +/- 3) were lower compared to the non mTORi (27 +/- 5) group (P = 0.04). We found that EPC colony-forming capacity was higher in HT patients who experienced moderate/severe rejection episodes. Patients on mTORi showed a reduced EPC colony count consistent with our previous findings of EPC cytotoxicity. Detection of circulating EPC function post-transplant may reliably identify patient risk level for subsequent allograft rejection and allow for appropriate adjustments to immunosuppression. Converting to mTORi therapy may reduce EPC function and provide a novel mechanism to prevent rejection and possibly attenuate the development of CAV.


Modification of human thrombin: effect on thrombomodulin binding.
Thrombomodulin, an endothelial cell protein, binds thrombin with high affinity and alters thrombin from a procoagulant to an anticoagulant molecule. In this study, chemical and/or proteolytic modification of thrombin was carried out to identify the essential components required for its interaction with thrombomodulin. Modification of thrombin at the catalytic site serine and histidine residues, with Diisopropylfluorophosphate and Tosyl-L-lysine chloromethyl ketone, resulted in loss of clotting and amidolytic activity. Both Diisopropyl phosphoryl-thrombin and Tosyl-L-chloromethyl ketone-thrombin inhibited native-thrombin: thrombomodulin catalyzed protein C activation with Ki values of 5 nM and 6 nM respectively indicating no loss of affinity for thrombomodulin. Oxidation of tryptophan residues with N-bromosuccinimide or iodination of tyrosine residues of thrombin led to reduced clotting and amidolytic activity as well as a reduced ability to interact with thrombomodulin. Modification of arginine residues with Phenylglyoxal and 2,3,Butanedione led to loss of thrombomodulin binding affinity. Limited proteolysis of thrombin by trypsin yielded the derivative beta-thrombin which had also lost its ability to interact with thrombomodulin. Deglycosylation of thrombin did not alter its binding affinity for thrombomodulin. These results indicate that one or more tryptophan, arginine and tyrosine residues are essential for the recognition of thrombin by thrombomodulin whilst the carbohydrate side chain and the active site residues of the thrombin molecule are not involved in thrombomodulin binding.


In vitro and in vivo efficacy of PEGylated diisopropyl fluorophosphatase (DFPase).
Highly toxic organophosphorus compounds that irreversibly inhibit the enzyme acetycholinesterase (AChE), including nerve agents like tabun, sarin, or soman, still pose a credible threat to civilian populations and military personnel. New therapeutics that can be used as a pretreatment or after poisoning with these compounds, complementing existing treatment schemes such as the use of atropine and AChE reactivating oximes, are currently the subject of intense research. A prominent role among potential candidates is taken by enzymes that can detoxify nerve agents by hydrolysis. Diisopropyl fluorophosphatase (DFPase) from the squid Loligo vulgaris is known to effectively hydrolyze DFP and the range of G-type nerve agents including sarin and soman. In the present work, DFPase was PEGylated to increase biological half-life, and to lower or avoid an immunogenic reaction and proteolytic digest. Addition of linear polyethylene glycol (PEG) chains was achieved using mPEG-NHS esters and conjugates were characterized by electrospray ionization--time of flight--mass specrometry (ESI-ToF-MS). PEGylated wildtype DFPase and a mutant selective for the more toxic stereoisomers of the agents were tested in vivo with rats that were challenged with a subcutaneous 3x LD(50) dose of soman. While wildtype DFPase prevented death only at extremely high doses, the mutant was able keep the animals alive and to minimize or totally avoid symptoms of poisoning. The results serve as a proof of principle that engineered variants of DFPase are potential candidates for in vivo use if substrate affinity can be improved or the turnover rate enhanced to lower the required enzyme dose.


Real world data of liver injury induced by immune checkpoint inhibitors in Japanese patients with advanced malignancies.
Liver injury induced by immune checkpoint inhibitors (ICIs) is an immune-related adverse event (irAE) whose incidence has increased with the broader use of ICIs in clinical practice. However, the incidental risk factors of immune-related liver injury are unknown. We investigated the clinical characteristics of immune-related liver injury. A total of 546 patients treated with ICIs for advanced malignancies between September 2014 and February 2019 were included retrospectively. Factors associated with immune-related liver injury were determined. Immune-related liver injury (≥ Grade 3) occurred in 29 (5.3%) patients (Grade 3, n = 20; Grade 4, n = 8; Grade 5, n = 1) during the follow-up period (median 153 days). The patterns of liver injuries were hepatocellular, n = 6 (20.7%); cholestatic, n = 17 (58.6%); and mixed, n = 6 (20.7%). The median period between the initial administration of ICIs and the incidence of irAEs was 52 days. Of 29 patients with immune-related liver injury (≥ Grade 3), four showed immune-related cholangitis with non-obstructive dilation of the bile ducts. Factors that were significantly associated with the incidence of immune-related liver injury in multivariate analysis were use of ipilimumab, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agent [hazard ratio [HR] 4.22, 95% confidence interval (CI) 1.65-10.80, P = 0.003], and fever over 38 °C within 24 h of initial ICI administration (HR 6.21, 95% CI 2.68-14.40, P < 0.001). We found that the use of ipilimumab and the presence of fever within 24 h of initial ICI administration were predictive factors for immune-related liver injury.


The Role of Latency and Task Complexity in Predicting Visual Search Behavior.
Latency in a visualization system is widely believed to affect user behavior in measurable ways, such as requiring the user to wait for the visualization system to respond, leading to interruption of the analytic flow. While this effect is frequently observed and widely accepted, precisely how latency affects different analysis scenarios is less well understood. In this paper, we examine the role of latency in the context of visual search, an essential task in data foraging and exploration using visualization. We conduct a series of studies on Amazon Mechanical Turk and find that under certain conditions, latency is a statistically significant predictor of visual search behavior, which is consistent with previous studies. However, our results also suggest that task type, task complexity, and other factors can modulate the effect of latency, in some cases rendering latency statistically insignificant in predicting user behavior. This suggests a more nuanced view of the role of latency than previously reported. Building on these results and the findings of prior studies, we propose design guidelines for measuring and interpreting the effects of latency when evaluating performance on visual search tasks.


De novo Donor-specific Anti-human Leukocyte Antigen Antibody and Its Outcome in Pediatric Renal Transplant Recipients: A Single-center Experience in India.
Development of de novo donor-specific anti-HLA antibody (dnDSA) is associated with poor graft survival in adults. However, there is a paucity of data about its prevalence and outcome in Indian children. We retrospectively assessed the proportion and spectrum of dnDSA and its outcome on antibody-mediated rejection (ABMR) and graft function. Children ≤18 years who were transplanted between November 2016 and October 2019 were included in this study. Pretransplant donor-specific antibody (DSA) was screened by complement-dependent cytotoxicity, flow cytometry crossmatch, and single antigen bead (SAB) class I and II by Luminex platform. Either antithymocyte globulin or basiliximab was used as induction. Tacrolimus, mycophenolate, and prednisolone were used for the maintenance of immunosuppression. SAB screening was done at 1, 3, 6 months, and yearly in seven children and at the time of acute graft dysfunction in eight. Mean fluorescence intensity ≥1000 was considered positive. Protocol biopsies were done at 3, 6, and 12 months and annually thereafter in seven children. Fifteen children, all males with a median age (interquartile range) of 13 years (11; 15.5) were analyzed. Only one child had pretransplant DSA who developed dnDSA posttransplant. Overall, 8 (53%) developed dnDSA over a median follow-up of 18 months. Seven (87%) had Class II, one Class I and 3 (37%) both Class I and II. Six had dQ and two had DR. All children with dnDSA had ABMR, of these two had subclinical rejection. DSAs persisted despite treatment, though graft function improved. Children with DSA and ABMR had lower graft function than those without DSA. The proportion of dnDSA was high in our study, majority against DQ. The detection of dnDSA prompted early diagnosis and treatment of ABMR.


Improved detection of regional melanoma metastasis using 18F-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide, a melanin-specific PET probe, by perilesional administration.
The efficacy of differing routes of administration of 18F-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide (18F-MEL050), a new benzamide-based PET radiotracer for imaging regional lymph node metastasis in melanoma, was assessed. B16-Black/6 metastatic melanoma cells harboring an mCherry transgene were implanted into the left-upper-foot surface of 49 C57 Black/6 mice as a model of popliteal lymph node (PLN) metastasis. Ultrasound scanning of the left PLN was performed at baseline and in combination with 18F-MEL050 PET on days 5, 9, and 14. Mice were divided into 2 groups to compare the results of tracer administration either subcutaneously at the tumor site (local) or in the lateral tail vein (systemic). After PET on each imaging day, 5 mice per group-including any with evidence of metastasis-were sacrificed for ex vivo validation studies including assessment of retained radioactivity and presence of the mCherry transgene as a surrogate of nodal tumor burden. Nine mice were judged as positive for PLN metastasis by ultrasound at day 5, and 8 PLNs were positive on 18F-MEL050 PET, 3 after systemic and 5 after local administration. Ex vivo analysis showed that ultrasound correctly identified 90% of positive PLNs, with 1 false-positive. 18F-MEL050 PET correctly identified 60% of positive PLNs after systemic administration and 100% after local administration with no false-positive results by either route. The average node-to-background ratio for positive PLNs was 6.8 in the systemic-administration group and correlated with disease burden. In the local-administration group, the mean uptake ratio was 48, without clear relation to metastatic burden. Additional sites of metastatic disease were also correctly identified by 18F-MEL050 PET. In addition to its potential for systemic staging, perilesional administration of 18F-MEL050 may allow sensitive and specific, noninvasive identification of regional lymph node metastasis in pigmented malignant melanomas.


Geometry of the Valgus Knee: Contradicting the Dogma of a Femoral-Based Deformity.
Realignment osteotomies of valgus knee deformities are usually performed at the distal femur, as valgus alignment is considered to be a femoral-based deformity. This dogma, however, has not been proven in a large patient population. Valgus malalignment may also be caused by a tibial deformity or a combined tibial and femoral deformity. The purposes of this study were (1) to analyze the coronal geometry of patients with valgus malalignment and identify the location of the underlying deformity and (2) to investigate the proportion of cases that require realignment osteotomy at the tibia, the femur, or both locations to avoid an oblique joint line. Cross-sectional study; Level of evidence, 3. The analysis included 420 standing full-leg radiographs of patients with valgus malalignment (mechanical femorotibial angle [mFTA], ≥4°). A systematic analysis of the coronal leg geometry was performed including the mFTA, mechanical lateral distal femoral angle (mLDFA), mechanical medial proximal tibial angle (mMPTA), and joint-line convergence angle (JLCA). The localization of the deformity was determined according to the malalignment test described by Paley, and patients were assigned to 1 of 4 groups: femoral-based valgus deformity, tibial-based valgus deformity, femoral- and tibial-based valgus deformity, or intra-articular/ligamentary-based valgus deformity. Subsequently, the ideal osteotomy site was identified with the goal of a postoperative change of the joint line of two different maximum values, ±2° and ±4°, from its physiological varus position of 3°. Measurements of the coronal alignment revealed a mean (±SD) mFTA of 7.4° ± 4.3° (range, 4°-28.2°). The mean mLDFA and mean mMPTA were 84.8° ± 2.4° and 90.9° ± 2.6°, respectively. The mean JLCA was 1.2° ± 3.1°. The majority (41.0%) of valgus deformities were tibial based, 23.6% were femoral based, 26.9% were femoral and tibial based, and 8.6% were intra-articular/ligamentary based. To achieve a straight-leg axis and an anatomic postoperative joint line with a tolerance of ±4°, the ideal site of a corrective osteotomy was tibial in 55.2% of cases and femoral in 19.5% of cases. A double-level osteotomy would be necessary in 25.2% of cases. With a tolerance of ±2°, the ideal osteotomy site was the proximal tibia in 41.0% of cases and the distal femur in 13.6% of cases; a double-level osteotomy would be necessary in 45.5% of cases. In contrast to the widespread belief that valgus malalignment is usually caused by a femoral deformity, this study found that valgus malalignment was attributable to tibial deformity in the majority of patients. In addition, a combined femoral- and tibial-based deformity was more common than an isolated femoral-based deformity. As a clinical consequence, varus osteotomies to treat lateral compartment osteoarthritis must be performed at the tibial site or as a double-level osteotomy in a relevant number of patients to avoid an oblique joint line.


Permeability of porous materials determined from the Euler characteristic.
We study the permeability of quasi-two-dimensional porous structures of randomly placed overlapping monodisperse circular and elliptical grains. Measurements in microfluidic devices and lattice Boltzmann simulations demonstrate that the permeability is determined by the Euler characteristic of the conducting phase. We obtain an expression for the permeability that is independent of the percolation threshold and shows agreement with experimental and simulated data over a wide range of porosities. Our approach suggests that the permeability explicitly depends on the overlapping probability of grains rather than their shape.


Medical students and AIDS: knowledge, attitudes and implications for education.
Second year medical students at a large midwestern university were surveyed about their attitudes regarding AIDS. Results indicated: (1) students with homosexual and/or HIV-positive friends were significantly more tolerant toward AIDS patients, (2) over half the students believed that treating AIDS patients may be hazardous and that their education had not prepared them to treat these patients safely, (3) one-third believed they had the right to refuse to treat AIDS patients, and (4) AIDS-phobia was significantly associated with homophobia. These data suggest that medical educators may need to help students overcome AIDS-phobia before some students will be able to incorporate instruction about AIDS since AIDS-phobia may inhibit this learning. Didactic instruction must be coupled with modeling by educators of non-prejudicial attitudes and strict adherence to medical professionalism.


The role of anti(myco)bacterial interventions in the management of IBD: is there evidence at all?
The etiology of IBD is unknown but may relate to an unidentified bacterial pathogen or an immunological reaction to gut microbiota. Antibiotics have therefore been proposed as a therapy for Crohn's disease (CD) and ulcerative colitis (UC). The aim of this review was to compel the evidence for the use of antibiotics in the treatment of IBD. We performed a systematic review of the literature regarding the use of antibiotics for inducing or maintaining remission in IBD. Current data are conflicting, but a recent systematic review of randomized controlled trials has shown a statistically significant effect of antibiotics being superior to placebo for active, perianal and quiescent CD and for active UC. These data have been poorly translated in clinical practice and the place of antibiotics is restricted to certain specific situations in the international guidelines. This is first linked to the difficulties in interpreting clinical trials because of their heterogeneity in study design, endpoints, type of antibiotic and concomitant therapies. The exception to this is the use of either ciprofloxacin or metronidazole for treating CD perianal fistulas. The pathology of CD, the likely primary and known secondary pathogens in this disease and the successful responses in animal models all plead for new trials of antibiotics in IBD. This is a call to select patients more carefully, and to continue antibiotics for longer than is customary. Beside antibiotics, new therapeutic approaches that can balance gut dysbiosis should be tested.


Anti-inflammatory effect of strawberry extract against LPS-induced stress in RAW 264.7 macrophages.
A common denominator in the pathogenesis of most chronic inflammatory diseases is the involvement of oxidative stress, related to ROS production by all aerobic organisms. Dietary antioxidants from plant foods represent an efficient strategy to counteract this condition. The aim of the present study was to evaluate the protective effects of strawberry extracts on inflammatory status induced by E. Coli LPS on RAW 264.7 macrophages by measuring the main oxidative and inflammatory biomarkers and investigating the molecular pathways involved. Strawberry pre-treatment efficiently counteracted LPS-induced oxidative stress reducing the amount of ROS and nitrite production, stimulating endogenous antioxidant enzyme activities and enhancing protection against lipid, protein and DNA damage (P < 0.05). Strawberry pre-treatment exerted these protective effects primarily through the activation of the Nrf2 pathway, which is markedly AMPK-dependent and also by the modulation of the NF-kB signalling pathway. Finally, an improvement in mitochondria functionality was also detected. The results obtained in this work highlight the health benefit of strawberries against inflammatory and oxidative stress in LPS-stimulated RAW 264.7 macrophages, investigating for the first time the possible involved molecular mechanisms.


Purification of chimeric heavy chain monoclonal antibody EG2-hFc using hydrophobic interaction membrane chromatography: an alternative to protein-A affinity chromatography.
Heavy chain monoclonal antibodies are being considered as alternative to whole-IgG monoclonal antibodies for certain niche applications. Protein-A chromatography which is widely used for purifying IgG monoclonal antibodies is also used for purifying heavy chain monoclonal antibodies as these molecules possess fully functional Fc regions. However, the acidic conditions used to elute bound antibody may sometimes also leach protein-A, which is immunotoxic. Low pH conditions also tend to make the mAb molecules unstable and prone to aggregation. Moreover, protein-A affinity chromatography does not remove aggregates already present in the feed. Hydrophobic interaction membrane chromatography (or HIMC) has already been studied as an alternative to protein-A chromatography for purifying whole-IgG monoclonal antibodies. This paper describes the use of HIMC for capturing a humanized chimeric heavy chain monoclonal antibody (EG2-hFC). Binding and eluting conditions were suitably optimized using pure EG2-hFC. Based on this, an HIMC method was developed for capture of EG2-hFC directly from cell culture supernatant. The EG2-hFc purity obtained in this single-step process was high. The glycan profiles of protein-A and HIMC purified monoclonal antibody samples were similar, clearly demonstrating that both techniques captured similarly glycosylated population of EG2-hFc. Moreover, this technique was able to resolve aggregates from monomeric form of the EG2-hFc.


Cervical ribs: a common variant overlooked in CT imaging.
Cervical ribs are congenital variants that are known to cause TOS or brachial plexopathy in up to 10% of the affected individuals. We investigated how often cervical ribs are present on cervical spine CT scans to determine the incidence in humans and the percentage of reported cervical ribs. Cervical spine CT scans and the reports of 3404 consecutive adult patients were retrospectively reviewed to determine the presence of cervical ribs and whether they had been reported. Cervical ribs were found in 2.0% (67/3404) of the population. Of the 67 patients with cervical ribs, 27 (40.3%) had bilateral ribs. The prevalence of cervical ribs in women was twice that in men, 2.8% (39/1414) versus 1.4% (28/1990). Although African Americans accounted for 50.1% (1706/3404) and whites, 41.2% (1402/3404) of the patient population, African Americans were 70.1% (47/67) of patients with cervical ribs, whereas whites were 26.9% (18/67). Radiologists commented on 25.5% (24/94) of the cervical ribs in 25.4% (27/67) of patients. The prevalence of cervical ribs in the human population has been a source of uncertainty due to the degree of difficulty that comes in detecting this often subtle congenital variation. In our sample, the prevalence was 2.0% of patients. Our study determined that cervical ribs are underreported in patients undergoing cervical spine CT. Given the potential clinical implications of these anatomic variants, neuroradiologists must be more meticulous in identifying cervical ribs when reviewing cervical spine CT scans.


Intense thermal terahertz-to-infrared emission from random metallic nanostructures under femtosecond laser irradiation.
We report intense (~10 mW), ultra-broadband (~150 THz wide), terahertz-to-infrared, Gaussian-wavefront emission from nanopore-structured metallic thin films under femtosecond laser pulse irradiation. The proposed underlying mechanism is thermal radiation. The nanostructures of the metal film are produced by random holes in the substrate. Under pulse-train femtosecond laser irradiation, we found dramatically enhanced optical absorption, with an absorptivity that was equal to as much as 95% of the metallic surface nanostructure, due to both an antireflection mechanism and dissipation of excited surface plasmon polaritons into the metal surface.


Guidelines for fitting multiple memory hearing aids.
Fitting guidelines to determine candidacy for multiple memory hearing aids and the choice of amplification for each memory are devised by reviewing studies on the selection of amplification for different listening conditions. The guideline for determining candidacy comprises three factors: (1) difficulty hearing in acoustically diverse conditions, (2) an average high-frequency hearing loss greater than about 55 dB HL, and (3) ability to vary the low-frequency gain by at least 5 dB. People who meet all three criteria are highly likely to benefit from multiple memories. People who meet criteria 1 and 2 or 1 and 3 are possible candidates. The guideline for determining the amplification characteristics needed for each memory also enables the fitter to determine the number of memories needed. The following recommendations for amplification characteristic for various listening conditions are based on the literature review: linear amplification with the prescribed National Acoustic Laboratories' (NAL) frequency response is recommended for listening to speech in quiet; substantial high-frequency compression is recommended for ease of understanding two voices that differed by 10 dB in overall level; a linear response steeper than the NAL response is recommended for ease of understanding speech in a low-frequency background noise; low-frequency compression is recommended to reduce annoyance of low-frequency background noise; and a linear response flatter than the NAL response is recommended for listening in high-frequency background noise, and possibly for listening to music.


Hydration Phase Diagram of Clay Particles from Molecular Simulations.
Adsorption plays a fundamental role in the behavior of clays. Because of the confinement between solid clay layers on the nanoscale, adsorbed water is structured in layers, which can occupy a specific volume. The transition between these states is intimately related to key features of clay thermo-hydro-mechanical behavior. In this article, we consider the hydration states of clays as phases and the transition between these states as phase changes. The thermodynamic formulation supporting this idea is presented. Then, the results from grand canonical Monte Carlo simulations of sodium montmorillonite are used to derive hydration phase diagrams. The stability analysis presented here explains the coexistence of different hydration states at clay particle scale and improves our understanding of the irreversibilities of clay thermo-hydro-mechanical behavior. Our results provide insights into the mechanics of the elementary constituents of clays, which is crucial for a better understanding of the macroscopic behavior of clay-rich rocks and soils.


Purification and properties of an aryl acylamidase of Bacillus sphaericus, catalyzing the hydrolysis of various phenylamide herbicides and fungicides.
From Bacillus sphaericus ATCC 12123 an aryl acylamidase (EC 22.214.171.124) was purified to homogeneity by ion exchange chromatography, gel filtration, and polyacrylamide gel electrophoresis. The enzyme is inducible by various phenylamides of the acylanilide, phenylcarbamate, and methoxysubstituted phenylurea type. It has a molecular weight of 75,000. Enzyme activity was inhibited by sulfhydryl reagents, several metal ions, and 3,4-dichloroaniline (a product of linuron degradation). A requirement for divalent metal ions in enzyme activity could not be demonstrated. In the presence of 6 M urea an irreversible inactivation of the enzyme occurred. The hydrolysis of L-alanine-4-nitroanilide was competitively inhibited by puromycin.


Prevalence and diversity of Hepatozoon in native and exotic geckos from Brazil.
Hepatozoon is a genus of hemogregarines constituting the most widespread and common reptile hemoparasite. Although various molecular assessments of these parasites have been conducted in lizards from Africa and Europe, similar studies are needed for South American lizards. Through amplification and sequencing of fragments of the 18S rRNA gene, we assess the prevalence of Hepatozoon parasites in 230 geckos from South America, including the endemic species Hemidactylus agrius, Hemidactylus brasilianus, Lygodactylus klugei, Phyllopezus pollicaris, Phyllopezus periosus, and an exotic species, Hemidactylus mabouia . We found an overall low prevalence of Hepatozoon infection (7/230, 3%) with only 3 of the 6 host species infected with Hepatozoon ( Hemidactylus mabouia , P. pollicaris, and P. periosus). Within the 7 infected host samples, 5 genetically distinct lineages of Hepatozoon parasites were identified, only 1 of which was similar to previously published haplotypes. Thus, although prevalence is low, genetically based diversity of Hepatozoon in geckos from South America is very high. Three of these lineages appear basal to 1 of the major clades of Hepatozoon, suggesting that this clade might have originated in South America, and thereby indicating a potential phylogeographic pattern that had not been previously identified. Future studies should assess the distribution and competence of invertebrate hosts in the regions analyzed, and Hepatozoon diversity in other less well-known regions of the world.


Association of fathers' feeding practices and feeding style on preschool age children's diet quality, eating behavior and body mass index.
The associations of parental feeding practices and feeding style with childhood obesity have gained more attention in the literature recently; however, fathers are rarely included within these studies. The aim of this research was to determine the relationship of paternal feeding practices on child diet quality, weight status, and eating behavior, and the moderating effect of paternal feeding style on these relationships in preschool age children. This study included a one-time, one-on-one interview with biological fathers of preschoolers (n = 150) to assess feeding practices (Child Feeding Questionnaire), feeding style (Caregiver Feeding Style Questionnaire), child eating behaviors (Child Eating Behavior Questionnaire), and diet quality (24 hour recall, Healthy Eating Index). Height and weight for each father and child were also measured and Body Mass Index (BMI) or BMI z-score calculated. Linear regression was used to test the relationship between paternal feeding practices, style and child diet quality and/or body weight. Overall, the findings revealed that a father's feeding practices and feeding style are not associated with children's diet quality or weight status. However, child eating behaviors are associated with child BMI z-score and these relationships are moderated by paternal feeding practices. For example, child satiety responsiveness is inversely (β = -.421, p = 0.031) associated with child BMI z-score only if paternal restriction scores are high. This relationship is not significant when paternal restriction scores are low (β = -.200, p = 0.448). These results suggest that some child appetitive traits may be related to child weight status when exposed to certain paternal feeding practices. Future studies should consider the inclusion of fathers as their feeding practices and feeding style may be related to a child's eating behavior.


Requirement for calcium ions in acetylcholine-stimulated phosphodiesteratic cleavage of phosphatidyl-myo-inositol 4,5-bisphosphate in rabbit iris smooth muscle.
1. The mechanism of acetylcholine-stimulated breakdown of phosphatidyl-myo-inositol 4,5-bisphosphate and its dependence on extracellular Ca(2+) was investigated in the rabbit iris smooth muscle. 2. Acetylcholine (50mum) increased the breakdown of phosphatidylinositol bisphosphate in [(3)H]inositol-labelled muscle by 28% and the labelling of phosphatidylinositol by 24% of that of the control. Under the same experimental conditions there was a 33 and 48% increase in the production of (3)H-labelled inositol trisphosphate and inositol monophosphate respectively. Similarly carbamoylcholine and ionophore A23187 increased the production of these water-soluble inositol phosphates. Little change was observed in the (3)H radioactivity of inositol bisphosphate. 3. Both inositol trisphosphatase and inositol monophosphatase were demonstrated in subcellular fractions of this tissue and the specific activity of the former was severalfold higher than that of the latter. 4. The acetylcholine-stimulated production of inositol trisphosphate and inositol monophosphate was inhibited by atropine (20mum), but not tubocurarine (100mum); and it was abolished by depletion of extracellular Ca(2+) with EGTA, but restored on addition of low concentrations of Ca(2+) (20mum). 5. Calcium-antagonistic agents, such as verapamil (20mum), dibenamine (20mum) or La(3+) (2mm), also abolished the production of the water-soluble inositol phosphates in response to acetylcholine. 6. Release of inositol trisphosphate from exogenous phosphatidylinositol bisphosphate by iris muscle microsomal fraction (;microsomes') was stimulated by 43% in the presence of 50mum-Ca(2+). 7. The results indicate that increased Ca(2+) influx into the iris smooth muscle by acetylcholine and ionophore A23187 markedly activates phosphatidylinositol bisphosphate phosphodiesterase and subsequently increases the production of inositol trisphosphate and its hydrolytic product inositol monophosphate. The marked increase observed in the production of inositol monophosphate could also result from Ca(2+) activation of phosphatidylinositol phosphodiesterase. However, there was no concomitant decrease in the (3)H radioactivity of this phospholipid.


The mosaic structure of the mcyABC operon in Microcystis.
An extensive study of the mcyABC genes and regions flanking the mcy gene cluster was performed in naturally occurring Microcystis strains. Lack of methylation in strains producing only desmethyl(7)-microcystin was found to be associated with point mutations in substrate-binding sequence motifs of the N-methyltransferase (NMT) domain in McyA. Multiple recombination events giving rise to 'phylogenetic mosaics' were detected within the NMT-domain-encoding mcyA sequences and the adenylation (A) domain sequences of mcyB and mcyC. Recombination leading to exchanges between the mcyB and mcyC regions encoding A domains in modules McyB1 and McyC was also detected. A previously reported replacement of the A domain in McyB1 was found to involve the region between the conserved motifs A3 and A8/A9. In all microcystin-producing strains the mcy gene cluster was flanked by the genes uma1 and dnaN. Clear indications of recombination, an insertion element and footprints of IS elements were found in the dnaN-mcyJ intergenic region. Among the non-microcystin producers, uma1 and dnaN were linked in some, but not all strains. Most non-producing strains lacked all mcy genes, while one strain possessed a partially deleted mcy operon. Our results show that frequent horizontal gene transfer events in addition to point mutations and insertions/deletions contribute to variation in the mcy gene cluster.


Physical activity over the life course and its association with cognitive performance and impairment in old age.
To determine how physical activity at various ages over the life course is associated with cognitive impairment in late life. Cross-sectional study. Four U.S. sites. Nine thousand three hundred forty-four women aged 65 and older (mean 71.6) who self-reported teenage, age 30, age 50, and late-life physical activity. Logistic regression was used to determine the association between physical activity status at each age and likelihood of cognitive impairment (modified Mini-Mental State Examination (mMMSE) score >1.5 standard deviations below the mean, mMMSE score</=22). Models were adjusted for age, education, marital status, diabetes mellitus, hypertension, depressive symptoms, smoking, and body mass index. Women who reported being physically active had a lower prevalence of cognitive impairment in late life than women who were inactive at each time (teenage: 8.5% vs 16.7%, adjusted odds ratio (AOR)=0.65, 95% confidence interval (CI)=0.53-0.80; age 30: 8.9% vs 12.0%, AOR=0.80, 95% CI=0.67-0.96); age 50: 8.5% vs 13.1%, AOR=0.71, 95% CI=0.59-0.85; old age: 8.2% vs 15.9%, AOR=0.74, 95% CI=0.61-0.91). When the four times were analyzed together, teenage physical activity was most strongly associated with lower odds of late-life cognitive impairment (OR=0.73, 95% CI=0.58-0.92). However, women who were physically inactive as teenagers and became active in later life had lower risk than those who remained inactive. Women who reported being physically active at any point over the life course, especially as teenagers, had a lower likelihood of cognitive impairment in late life. Interventions should promote physical activity early in life and throughout the life course.


Database combinations to retrieve systematic reviews in overviews of reviews: a methodological study.
When conducting an Overviews of Reviews on health-related topics, it is unclear which combination of bibliographic databases authors should use for searching for SRs. Our goal was to determine which databases included the most systematic reviews and identify an optimal database combination for searching systematic reviews. A set of 86 Overviews of Reviews with 1219 included systematic reviews was extracted from a previous study. Inclusion of the systematic reviews was assessed in MEDLINE, CINAHL, Embase, Epistemonikos, PsycINFO, and TRIP. The mean inclusion rate (% of included systematic reviews) and corresponding 95% confidence interval were calculated for each database individually, as well as for combinations of MEDLINE with each other database and reference checking. Inclusion of systematic reviews was higher in MEDLINE than in any other single database (mean inclusion rate 89.7%; 95% confidence interval [89.0-90.3%]). Combined with reference checking, this value increased to 93.7% [93.2-94.2%]. The best combination of two databases plus reference checking consisted of MEDLINE and Epistemonikos (99.2% [99.0-99.3%]). Stratification by Health Technology Assessment reports (97.7% [96.5-98.9%]) vs. Cochrane Overviews (100.0%) vs. non-Cochrane Overviews (99.3% [99.1-99.4%]) showed that inclusion was only slightly lower for Health Technology Assessment reports. However, MEDLINE, Epistemonikos, and reference checking remained the best combination. Among the 10/1219 systematic reviews not identified by this combination, five were published as websites rather than journals, two were included in CINAHL and Embase, and one was included in the database ERIC. MEDLINE and Epistemonikos, complemented by reference checking of included studies, is the best database combination to identify systematic reviews on health-related topics.


Two new antioxidant actinosporin analogues from the calcium alginate beads culture of sponge-associated Actinokineospora sp. strain EG49.
Marine sponge-associated actinomycetes represent an exciting new resource for the identification of new and novel natural products . Previously, we have reported the isolation and structural elucidation of actinosporins A (1) and B (2) from Actinokineospora sp. strain EG49 isolated from the marine sponge Spheciospongia vagabunda. Herein, by employing different fermentation conditions on the same microorganism, we report on the isolation and antioxidant activity of structurally related metabolites, actinosporins C (3) and D (4). The antioxidant potential of actinosporins C and D was demonstrated using the ferric reducing antioxidant power (FRAP) assay. Additionally, at 1.25 μM, actinosporins C and D showed a significant antioxidant and protective capacity from the genomic damage induced by hydrogen peroxide in the human promyelocytic (HL-60) cell line.


Chronic hepatitis delta: A state-of-the-art review and new therapies.
Chronic delta hepatitis is the most severe form of viral hepatitis affecting nearly 65 million people worldwide. Individuals with this devastating illness are at higher risk for developing cirrhosis and hepatocellular carcinoma. Delta virus is a defective RNA virus that requires hepatitis B surface antigen for propagation in humans. Infection can occur in the form of a co-infection with hepatitis B, which can be self-limiting, vs superinfection in a patient with established hepatitis B infection, which often leads to chronicity in majority of cases. Current noninvasive tools to assess for advanced liver disease have limited utility in delta hepatitis. Guidelines recommend treatment with pegylated interferon, but this is limited to patients with compensated disease and is efficacious in about 30% of those treated. Due to limited treatment options, novel agents are being investigated and include entry, assembly and export inhibitors of viral particles in addition to stimulators of the host immune response. Future clinical trials should take into consideration the interaction of hepatitis B and hepatitis D as suppression of one virus can lead to the activation of the other. Also, surrogate markers of treatment efficacy have been proposed.


Current status of β-lactam antibiotic use and characterization of β-lactam-resistant Escherichia coli from commercial farms by integrated broiler chicken operations in Korea.
β-Lactam antibiotics are one of the most clinical importance in human and veterinary medicine because they are used for both preventive and therapeutic purposes against several gram-positive, gram-negative, and anaerobic organisms. In this study, it was confirmed that β-lactams (81.1%) were found to be significantly prescribed the most among 74 farms in 5 integrated broiler operations, and single prescription (84.6%), 2-day (41.5%) or 3-day (40.0%) administration, and 15 to 22 d of age (67.7%) administration was significantly higher in the farms (P < 0.05). Among the E. coli isolated from 74 farms in 5 integrated broiler operations, β-lactam-resistant E. coli isolates were detected more frequently in fecal sample (94.6%) than in dust sample (60.8%) (P < 0.05). The prevalence of MDR in β-lactam-resistant isolates, ranging from 88.1 to 96.5%, was significantly higher than that in non-β-lactam-resistant isolates (P < 0.05), without significant differences among operations. Of 466 β-lactam-resistant isolates, 432 (92.7%) isolates harbored β-lactamase genes. The non-extended-spectrum β-lactamase (ESBL) gene blaTEM-1 (81.8%) showed the highest prevalence among isolates, followed by the non-ESBL gene blaTEM-135 (6.4%) (P < 0.05). Five ESBL genes, SHV-12, OXA-1, CTX-M-27, CTX-M-55, and CTX-M-65, were found in 0.9 to 6.0% of the isolates. The pAmpC gene blaCMY-2 was detected in 17 isolates (3.6%). These results suggest that feces and dust are important reservoirs of antimicrobial-resistant bacteria, highlighting the need to strengthen farm management regulations, such as cleaning, disinfection, and litter disposal and to reduce the use of antibiotics in broiler operations.


TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.
Recently, we marked TRIO for the first time as a candidate gene for intellectual disability (ID). Across diverse vertebrate species, TRIO is a well-conserved Rho GTPase regulator that is highly expressed in the developing brain. However, little is known about the specific events regulated by TRIO during brain development and its clinical impact in humans when mutated. Routine clinical diagnostic testing identified an intragenic de novo deletion of TRIO in a boy with ID. Targeted sequencing of this gene in over 2300 individuals with ID, identified three additional truncating mutations. All index cases had mild to borderline ID combined with behavioral problems consisting of autistic, hyperactive and/or aggressive behavior. Studies in dissociated rat hippocampal neurons demonstrated the enhancement of dendritic formation by suppressing endogenous TRIO, and similarly decreasing endogenous TRIO in organotypic hippocampal brain slices significantly increased synaptic strength by increasing functional synapses. Together, our findings provide new mechanistic insight into how genetic deficits in TRIO can lead to early neuronal network formation by directly affecting both neurite outgrowth and synapse development.


Ergonomic concerns with lightbar guidance displays.
This article reviews some ergonomic factors associated with agricultural guidance displays. Any technology or management decision that improves the efficiency of an agricultural operation can be considered an aspect of precision farming. Agricultural guidance displays are one such tool because they help to reduce guidance error (i.e., skipping and overlapping of implements within the field), which result in improper application of crop inputs at increased cost. Although each of the guidance displays currently available functions using a different principle, their key objective is to communicate useful guidance information to the operator of the agricultural machine. The case with which the operator obtains the required information depends on a number of ergonomic factors, such as color perceptibility, flash rate, attentional demand, display size, viewing distance, and height of placement of the display in the cab. Ergonomics can be defined as the application of knowledge to create a safe, comfortable, and effective work environment. Consequently, it is critical to consider ergonomics when designing guidance displays or when locating a display in the tractor cab. Without considering ergonomics, it is unlikely that the efficiency of the human-machine system can be optimized.


The Barley S-Adenosylmethionine Synthetase 3 Gene HvSAMS3 Positively Regulates the Tolerance to Combined Drought and Salinity Stress in Tibetan Wild Barley.
Drought and salinity are two of the most frequently co-occurring abiotic stresses. Despite recent advances in the elucidation of the effects of these stresses individually during the vegetative stage of plants, significant gaps exist in our understanding of the combined effects of these two frequently co-occurring stresses. Here, Tibetan wild barley XZ5 (drought tolerant), XZ16 (salt tolerant), and cultivated barley cv. CM72 (salt tolerant) were subjected to drought (D), salinity (S), or a combination of both treatments (D+S). Protein synthesis is one of the primary activities of the green part of the plant. Therefore, leaf tissue is an important parameter to evaluate drought and salinity stress conditions. Sixty differentially expressed proteins were identified by mass spectrometry (MALDI-TOF/TOF) and classified into 9 biological processes based on Gene Ontology annotation. Among them, 21 proteins were found to be expressed under drought or salinity alone; however, under D+S, 7 proteins, including S-adenosylmethionine synthetase 3 (SAMS3), were exclusively upregulated in drought-tolerant XZ5 but not in CM72. HvSAMS3 carries both N-terminal and central domains compared with Arabidopsis and activates the expression of several ethylene (ET)-responsive transcription factors. HvSAMS3 is mainly expressed in the roots and stems, and HvSAMS3 is a secretory protein located in the cell membrane and cytoplasm. Barley stripe mosaic virus-based virus-induced gene silencing (BSMV-VIGS) of HvSAMS3 in XZ5 severely compromised its tolerance to D+S and significantly reduced plant growth and K+ uptake. The reduced tolerance to the combined stress was associated with the inhibition of polyamines such as spermidine and spermine, polyamine oxidase, ethylene, biotin, and antioxidant enzyme activities. Furthermore, the exogenous application of ethylene and biotin improved the tolerance to D+S in BSMV-VIGS:HvSAMS3-inoculated plants. Our findings highlight the significance of HvSAMS3 in the tolerance to D+S in XZ5.


Measuring the equity of inpatient utilization in Chinese rural areas.
As an important outcome of the health system, equity in health service utilization has attracted an increasing amount of attention in the literature on health reform in China in recent years. The poor, who frequently require more services, are often the least able to pay, while the wealthy utilize disproportionately more services although they have less need. Whereas equity in health service utilization between richer and poorer populations has been studied in urban areas, the equity in health service utilization in rural areas has received little attention. With improving levels of economic development, the introduction of health insurance and increasing costs of health services, health service utilization patterns have changed dramatically in rural areas in recent years. However, previous studies have shown neither the extent of utilization inequity, nor which factors are associated with utilization inequity in rural China. This paper uses previously unavailable country-wide data and focuses on income-related inequity of inpatient utilization and its determinants in Chinese rural areas. The data for this study come from the Chinese National Health Services Surveys (NHSS) conducted in 2003 and 2008. To measure the level of inequity in inpatient utilization over time, the concentration index, decomposition of the concentration index, and decomposition of change in the concentration index are employed. This study finds that even with the same need for inpatient services, richer individuals utilize more inpatient services than poorer individuals. Income is the principal determinant of this pro-rich inpatient utilization inequity- wealthier individuals are able to pay for more services and therefore use more services regardless of need. However, rising income and increased health insurance coverage have reduced the inequity in inpatient utilization in spite of increasing inpatient prices. There remains a strong pro-rich inequity of inpatient utilization in rural China. However, a narrowing income gap between the rich and poor and greater access to health insurance has effectively reduced income inequality, equalizing access to care. This suggests that the most effective way to reduce the inequity is to narrow the gap of income between the rich and poor while adopting social risk protection.


Evaluation of very high- and very low-dose intravitreal aflibercept in patients with neovascular age-related macular degeneration.
To determine bioactivity and duration of effect of intravitreal aflibercept injection (also known as vascular endothelial growth factor Trap-Eye) for neovascular age-related macular degeneration (AMD). In this double-masked, phase 1 study, 28 patients with lesions ≤12 disc areas, ≥50% active choroidal neovascularization (CNV), and best corrected visual acuity (BCVA) ≤20/40 were randomized 1:1 to a single intravitreal injection of aflibercept 0.15 or 4 mg. The primary end point was the change from baseline in central retinal/lesion thickness (CR/LT) at week-8. Secondary outcomes were the change from baseline BCVA, the change in CNV lesion size and area of leakage, and proportion of patients requiring repeat injection at 8 weeks. Mean percent decrease in CR/LT for the 4-mg and 0.15-mg groups was, respectively, 34.2 versus 13.3 at week 4 (P=0.0065), 23.8 versus 5.9 at week 6 (P=0.0380), and 25.2% versus 11.3% at week 8 (P=0.150). The 4-mg group gained a mean of 4.5 letters in BCVA (6/14 patients gaining ≥10 letters) versus 1.1 letters in 0.15-mg group (1/14 gaining ≥10 letters) at week 8. Fewer patients needed retreatment in the 4-mg group at week 8. No serious adverse event or ocular inflammation was reported in either group. Intravitreal aflibercept 4 mg had a safety profile similar to that of the very low dose 0.15 mg, and was well-tolerated. The 4-mg dose significantly reduced foveal thickening at weeks 4 and 6, significantly improved BCVA at weeks 6, and reduced the need for repeat injection after 8 weeks compared with intravitreal aflibercept 0.15 mg in neovascular AMD patients.


Perfusion machines and hepatocellular carcinoma: a good match between a marginal organ and an advanced disease?
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers, is the second leading cause of cancer-related deaths and the leading cause of death in patients with cirrhosis. Liver transplantation (LT) represents the ideal treatment for selected patients as it removes both the tumor and the underlying cirrhotic liver with 5-year survival rates higher than 70%. Unfortunately, due to tumor characteristics, patient co-morbidities or shortage of organs available for transplant, only 20% of patients can undergo curative treatment. Ex situ machine perfusion (MP) is a technology recently introduced that might potentially improve organ preservation, allow graft assessment and increase the pool of available organs. The purpose of this review is to provide an update on the current role of ex situ liver MP in liver transplantation for HCC patients.


Development of a Ratiometric Tension Sensor Exclusively Responding to Integrin Tension Magnitude in Live Cells.
Integrin tensions are critical for cell mechanotransduction. By converting force to fluorescence, molecular tension sensors image integrin tensions in live cells with a high resolution. However, the fluorescence signal intensity results collectively from integrin tension magnitude, tension dwell time, integrin density, sensor accessibility, and so forth, making it highly challenging to specifically monitor the molecular force level of integrin tensions. Here, a ratiometric tension sensor (RTS) was developed to exclusively monitor the integrin tension magnitude. The RTS consists of two tension-sensing units that are coupled in series and always subject to the same integrin tension. These two units are activated by tension to fluoresce in separate spectra and with different activation rates. The ratio of their activation probabilities, reported by fluorescence ratiometric measurement, is solely determined by the local integrin tension magnitude. RTS responded sensitively to the variation of integrin tension magnitude in platelets and focal adhesions due to different cell plating times, actomyosin inhibition, or vinculin knockout. At last, RTS confirmed that integrin tension magnitude in platelets and focal adhesions decreases monotonically with the substrate rigidity, verifying the rigidity dependence of integrin tensions in live cells and suggesting that integrin tension magnitude could be a key biomechanical factor in cell rigidity sensing.


Correlation of DNA, RNA, and protein content by flow cytometry in normal and Coxiella burnetii-infected L929 cells.
L929 cell populations persistently infected for more than 600 days exhibited cell cycle distributions and generation times similar to those of uninfected cells. The RNA and protein contents of these long-term-infected cells, as determined by flow cytometry and correlated with the cell cycle, were likewise approximately the same as those in normal uninfected cells. Also, the ratios of RNA to DNA and RNA to protein of infected cells were not significantly different from those of normal cells. Collectively, these data indicate that the long-term-infected cells remained in a state of balanced growth and maintained normal cycle progression and division capacity, allowing for growth and proliferation of host cells and thus ensuring the propagation and persistence of the parasite.


Trypanosoma brucei transferrin receptor can bind C-lobe and N-lobe fragments of transferrin.
Transferrin (Tf) is a dumbbell-shaped iron transport protein composed of two homologous lobes (C-lobe and N-lobe) and is an essential growth factor for the protozoan parasite Trypanosoma brucei. The trypanosomal receptor for Tf uptake (TbTfR) is a heterodimeric complex that bears no structural similarity with the human Tf receptor. As a first step in identifying the region of Tf involved in binding to the TbTfR, C-lobe and N-lobe fragments were assessed for their capability to interact with the receptor. Preparations of C-lobe and N-lobe fragments were obtained by digestion of iron-loaded bovine Tf with proteinase K-agarose. The individual fragments were then purified by concanavalin A affinity chromatography. Uptake experiments with bloodstream forms of T. brucei demonstrated that both C-lobe and N-lobe fragments were ingested by the parasites. The uptake of the isolated lobes could be inhibited by an excess of Tf and vice versa. Dot blot binding assays showed that both C-lobe and N-lobe fragments were capable of binding to the TbTfR. Both isolated lobes were also able to support the growth of bloodstream forms of T. brucei when cultured in Tf-depleted medium. However, the C-lobe fragment was more efficiently taken up and more potent in supporting parasite growth. The results indicate that the interaction of Tf with the TbTfR is different from that with the human Tf receptor. This difference may be exploited for the development of agents specifically interfering with the binding of Tf to the TbTfR.


Cell surface Thy-1-cross-reactive glycoprotein in cultured PC12 cells: modulation by nerve growth factor and association with the cytoskeleton.
In cultured PC12 rat pheochromocytoma cells, nerve growth factor (NGF) selectively stimulated the incorporation of [3H]fucose into a glycoprotein of apparent Mr approximately 25,000, as determined by sodium dodecyl sulfate-gel electrophoresis. Neither dibutyryl cyclic adenosine 3':5'-monophosphate nor epidermal growth factor mimicked this effect. Using gradient gels, the affected protein was resolved into two closely migrating bands. Enhancement of labeling was present by 1 to 2 days of treatment with NGF and was maximal after 4 to 7 days. Short-term extraction of PC12 cell monolayer cultures with Triton X-100 left the 25,000-dalton glycoprotein associated with the detergent-resistant cytoskeletal fraction. The Mr approximately 25,000 glycoprotein was shown to be immunologically cross-reactive with Thy-1.1 antigen by indirect immunoprecipitation with monoclonal Thy-1.1 antibodies. Anti-Thy-1.1 labeling, as demonstrated by indirect immunofluorescence, was distributed on PC12 cell bodies and along neuritic processes and remained attached to the cytoskeleton as part of the surface lamina of cells treated and untreated with NGF. The selective increase of the Mr approximately equal to 25,000 glycoprotein in NGF-treated cultures was also paralleled by increases in material immunoprecipitated from fucose-labeled cells with anti Thy-1.1 monoclonal antibodies. Immunoprecipitations with extracts of [35S]methionine-labeled cultures indicated that NGF causes an increase in synthesis, rather than merely glycosylation, of the 25,000-dalton/Thy-1-cross-reactive protein. The effect of NGF on this protein was blocked by inhibitors of RNA synthesis, suggesting involvement of a transcription-dependent mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)


Quantifying the proteolytic release of extracellular matrix-sequestered VEGF with a computational model.
VEGF proteolysis by plasmin or matrix metalloproteinases (MMPs) is believed to play an important role in regulating vascular patterning in vivo by releasing VEGF from the extracellular matrix (ECM). However, a quantitative understanding of the kinetics of VEGF cleavage and the efficiency of cell-mediated VEGF release is currently lacking. To address these uncertainties, we develop a molecular-detailed quantitative model of VEGF proteolysis, used here in the context of an endothelial sprout. To study a cell's ability to cleave VEGF, the model captures MMP secretion, VEGF-ECM binding, VEGF proteolysis from VEGF165 to VEGF114 (the expected MMP cleavage product of VEGF165) and VEGF receptor-mediated recapture. Using experimental data, we estimated the effective bimolecular rate constant of VEGF165 cleavage by plasmin to be 328 M(-1) s(-1) at 25 degrees C, which is relatively slow compared to typical MMP-ECM proteolysis reactions. While previous studies have implicated cellular proteolysis in growth factor processing, we show that single cells do not individually have the capacity to cleave VEGF to any appreciable extent (less than 0.1% conversion). In addition, we find that a tip cell's receptor system will not efficiently recapture the cleaved VEGF due to an inability of cleaved VEGF to associate with Neuropilin-1. Overall, VEGF165 cleavage in vivo is likely to be mediated by the combined effect of numerous cells, instead of behaving in a single-cell-directed, autocrine manner. We show that heparan sulfate proteoglycans (HSPGs) potentiate VEGF cleavage by increasing the VEGF clearance time in tissues. In addition, we find that the VEGF-HSPG complex is more sensitive to proteases than is soluble VEGF, which may imply its potential relevance in receptor signaling. Finally, according to our calculations, experimentally measured soluble protease levels are approximately two orders of magnitude lower than that needed to reconcile levels of VEGF cleavage seen in pathological situations.


Influence of the flow rate during flushing on porcine multivisceral preservation.
The effect of flushing flow rate during multiple organ procurement (MOP) on viability of the liver, pancreas, and intestine were investigated in porcine multivisceral transplantation. Splanchnic organs were flushed in situ with 50 ml/kg of 4 degrees C UW solution via the aorta using a pump at a flow rate of 10, 30, or 50 ml/kg/min. After storage and transplantation, we assessed the clearance of hyaluronic acid (CHA) for hepatic endothelial cells function, liver enzymes, amylase, and histology. Two-day survival was 17% in the 10 ml/kg/min group and 67% in other groups. The former group had inadequate flushing out of the hepatic and intestinal grafts, resulting in aggravation of CHA and intestinal tissue injury. At the flow rate of 30 ml/kg/min, the viability and integrity of all organs were well maintained. We conclude that the optimal flushing flow rate would differ for each organ, therefore the common flow rate acceptable for any of the individual grafts should be applied in MOP.


Advanced age dissociates dual functions of the perirhinal cortex.
The perirhinal cortex (PRC) is proposed to both represent high-order sensory information and maintain those representations across delays. These cognitive processes are required for recognition memory, which declines during normal aging. Whether or not advanced age affects the ability of PRC principal cells to support these dual roles, however, is not known. The current experiment recorded PRC neurons as young and aged rats traversed a track. When objects were placed on the track, a subset of the neurons became active at discrete locations adjacent to objects. Importantly, the aged rats had a lower proportion of neurons that were activated by objects. Once PRC activity patterns in the presence of objects were established, however, both age groups maintained these representations across delays up to 2 h. These data support the hypothesis that age-associated deficits in stimulus recognition arise from impairments in high-order stimulus representation rather than difficulty in sustaining stable activity patterns over time.


Rambouillet and Romanov reciprocal breed effects on survival and growth traits of F1 lambs and on reproductive traits of F1 ewes.
Objectives were to estimate reciprocal effects of Romanov and Rambouillet breeds on survival, growth, and reproductive traits of F1 progeny and direct breed effects (Suffolk and Composite - ½ Columbia, ¼ Hampshire, and ¼ Suffolk) on survival and growth traits of the subsequent terminally sired lambs. Mature Rambouillet ewes (n = 243) were exposed to 20 Romanov rams over two seasons producing 621 lambs for evaluation of growth and survival traits with 274 F1 ewes being evaluated for reproduction traits through 4 yr of age. Similarly, mature Romanov ewes (n = 116) were exposed to 20 Rambouillet rams producing 601 lambs for evaluation of growth and survival traits with 176 F1 ewes being evaluated for reproduction traits through 4 yr of age. A total of 433 of those F1 ewes produced 3,431 lambs (1,552 litters) from 1,634 exposures to terminal sires over 4 yr. Terminal sires consisted of 38 Suffolk and 44 Composite rams. Reciprocal crossbred ewe lambs were produced from dramatically different uterine and neonatal environments, with litter size at birth from Romanov dams exceeding those from Rambouillet dams by 1.52 lambs (P < 0.001) and birth weight of lambs from Romanov dams averaged 3.41 kg compared with 4.26 kg from Rambouillet dams. Differences in BW were still evident at 140 d (P < 0.001) for dam-reared lambs. However, reciprocal ewe first breeding BW of both types were similar (P = 0.38). Minimal differences were observed in performance of reciprocal cross ewes through 4 yr for productivity, longevity, or progeny growth and survival. One exception was BW at 140 d where an interaction of dam breed with terminal sire breed reached significance for both dam-reared (P = 0.05) and nursery-reared (P = 0.02) lambs. This interaction was due to the lower weight of Composite-sired lambs out of reciprocal cross ewes born from Rambouillet dams. Composite rams increased number born (P < 0.01) and number weaned (P < 0.05) of the reciprocal cross ewes. Suffolk rams increased (P < 0.001) BW and growth rates from birth to 140 d of terminal progeny. Thus, there were little cumulative differences accrued over the 4 yr and no differences were detected for cumulative kilogram of lamb generated at 140 d per ewe exposed. The practical outcome of this evaluation was that performance levels of both types of Romanov crossbred ewes was similar allowing the industry to produce the desired crossbred ewes without needing large purebred ewe flocks of the less numerous Romanov breed.


Desymmetrization of a meso-diol complex derived from [Cr(CO)3(eta6-5,8-naphthoquinone)]: use of new diamine acylation catalysts.
[Cr(CO)3(naphthoquinone)](1), prepared in a three-step sequence starting from 1,4-dihydroxynaphthalene, was reduced to the corresponding meso-dihydronaphthalene syn-diol complex and the latter was desymmetrized to give the mono-acyl complex with 99% ee via asymmetric acylation catalyzed by the two new and easily accessed chiral diamines 7 and 8.


Regulation of the high-affinity ammonium transporter (BnAMT1;2) in the leaves of Brassica napus by nitrogen status.
Substantial concentrations of NH4+ are found in the apoplast of the leaves of Brassica napus. Physiological studies on isolated mesophyll protoplasts with 15NH4+ revealed the presence of a high-affinity ammonium transporter that shared physiological similarity to the high-affinity NH4+ transporters in Arabidopsis thaliana (AtAMT1;3). PCR techniques were used to isolate a full-length clone of a B. napus homologue of AMT1 from shoot mRNA which showed 97% similarity to AtAMT1;3. The full-length cDNA when cloned into the yeast expression vector pFL61 was able to complement a yeast mutant unable to grow on media with NH4+ as the sole nitrogen source. Regulatory studies with detached leaves revealed a stimulation of both NH4+ uptake and expression of mRNA when the leaves were supplied with increasing concentrations of NH4+. Withdrawal of NH4+ supply for up to 96 h had little effect on mRNA expression or NH4+ uptake; however, plants grown continuously at high NH4+ levels exhibited decreased mRNA expression. BnAMT1;2 mRNA expression was highest when NH4+ was supplied directly to the leaf and lowest when either glutamine or glutamate was supplied to the leaves, which directly paralleled chloroplastic glutamine synthetase (GS2) activity in the same leaves. These results provide tentative evidence that BnAMT1;2 may be regulated by similar mechanisms to GS2 in leaves.


Prevalence of hereditary hemochromatosis in a Massachusetts corporation: is Celtic origin a risk factor?
The prevalence of homozygous hereditary hemochromatosis (HHC) is estimated at 1:250 in Caucasian adults. Little is known about ethnic subpopulations that might be at increased risk for this disease. HLA data have suggested a Celtic origin for HHC. Screening for HHC was offered to all employees of the Massachusetts Polaroid Corporation. Participants with a transferrin saturation of >55% or >45% and an elevated serum ferritin concentration on two screenings were referred for liver biopsy. The diagnosis of HHC was based on histological criteria, quantitative hepatic iron determination, hepatic iron index, and the phlebotomy requirement for iron depletion. Participants completed a questionnaire regarding their ethnic background. Two thousand two hundred ninety-four employees were screened, and 5 cases of HHC were detected. All 5 cases involved Caucasian men, yielding a prevalence of 1:395 for the Caucasian population. Four of the 5 cases were of 100% British-Irish ancestry based on the country of origin of their grandparents. Additional analysis revealed that the majority of grandparents of all 4 individuals came from Ireland or Wales. The exact two-tailed trend test showed a significant association of HHC with Celtic background (P = .012). The estimated cost of screening per patient identified was $18,041. Polaroid Corporation has a high representation of employees of British-Irish ancestry. Our data suggest that they are at high risk for developing HHC. A significant association of HHC with Celtic ancestry was found in this subpopulation, supporting the concept of a Celtic origin for this disease.


Obesity and overweight in Bangladeshi children and adolescents: a scoping review.
Obesity and overweight in children and adolescents is an emerging public health concern alongside under-nutrition in low and middle income countries. Our aim was to conduct a scoping review of literature to ascertain what is known about childhood and adolescent overweight and/or obesity in Bangladesh. Using the scoping review based on York methodology, a comprehensive search of published academic articles, conference proceedings and grey literature was carried out through PubMed, BanglaJOL, Google and Google scholar limited to English-written papers. We summarized prevalence, risk factors and health outcomes of obesity/overweight in young children and adolescents aged between 0 to 19 years old in Bangladesh and highlighted use of different reference standards to measure childhood obesity. In total 21 studies met the inclusion criteria. Nearly all of the reviewed articles used data from cross sectional studies, while only two used case-control design. Overall thirteen studies (62%) were primary research and eight (38%) included secondary data. Studies indicated an increasing trend in childhood obesity over time. Prevalence ranged from less than 1% to 17.9% based on different reference standards, with higher percentage amongst urban children across different age groups and sexes. This review demonstrated paucity of comprehensive literature on childhood obesity in Bangladesh, which might be explored through population-based prospective studies based on strong methodology and uniform reference standards. Sustainable and scalable preventative measures targeting high risk groups are required to avoid further rise.


Aurora kinases: structure, functions and their association with cancer.
Aurora kinases are a recently discovered family of kinases (A, B & C) consisting of highly conserved serine\threonine protein kinases found to be involved in multiple mitotic events: regulation of spindle assembly checkpoint pathway, function of centrosomes and cytoskeleton, and cytokinesis. Aberrant expression of Aurora kinases may lead to cancer. For this reason the Aurora kinases are potential targets in the treatment of cancer. In this review we discuss the biology of these kinases: structure, function, regulation and association with cancer. A literature search. Many of the multiple functions of mitosis are mediated by the Aurora kinases. Their aberrant expression can lead to the deregulation of cell division and cancer. For this reason, the Aurora kinases are currently one of the most interesting targets for cancer therapy. Some Aurora kinase inhibitors in the clinic have proven effectively on a wide range of tumor types. The clinical data are very encouraging and promising for development of novel class of structurally different Aurora kinase inhibitors. Hopefully the Aurora kinases will be potentially useful in drug targeted cancer treatment.


Machine learning model development for quantitative analysis of CT heterogeneity in canine hepatic masses may predict histologic malignancy.
Tumor heterogeneity is a well-established marker of biologically aggressive neoplastic processes and is associated with local recurrence and distant metastasis. Quantitative analysis of CT textural features is an indirect measure of tumor heterogeneity and therefore may help predict malignant disease. The purpose of this retrospective, secondary analysis study was to quantitatively evaluate CT heterogeneity in dogs with histologically confirmed liver masses to build a predictive model for malignancy. Forty dogs with liver tumors and corresponding histopathologic evaluation from a previous prospective study were included. Triphasic image acquisition was standardized across dogs and whole liver and liver mass were contoured on each precontrast and delayed postcontrast dataset. First-order and second-order indices were extracted from contoured regions. Univariate analysis identified potentially significant indices that were subsequently used for top-down model construction. Multiple quadratic discriminatory models were constructed and tested, including individual models using both postcontrast and precontrast whole liver or liver mass volumes. The best performing model utilized the CT features voxel volume and uniformity from postcontrast mass contours; this model had an accuracy of 0.90, sensitivity of 0.67, specificity of 1.0, positive predictive value of 1.0, negative predictive value of 0.88, and precision of 1.0. Heterogeneity indices extracted from delayed postcontrast CT hepatic mass contours were more informative about tumor type compared to indices from whole liver contours, or from precontrast hepatic mass and whole liver contours. Results demonstrate that CT radiomic feature analysis may hold clinical utility as a noninvasive method of predicting hepatic malignancy and may influence diagnostic or therapeutic approaches.


Functional impairment of bone formation in the pathogenesis of osteoporosis: the bone marrow regenerative competence.
The skeleton is a high-renewal organ that undergoes ongoing cycles of remodeling. The regenerative bone formation arm ultimately declines in the aging, postmenopausal skeleton, but current therapies do not adequately address this deficit. Bone marrow is the primary source of the skeletal anabolic response and the mesenchymal stem cells (MSCs), which give rise to bone matrix-producing osteoblasts. The identity of these stem cells is emerging, but it now appears that the term 'MSC' has often been misapplied to the bone marrow stromal cell (BMSC), a progeny of the MSC. Nevertheless, the changes in BMSC phenotype associated with age and estrogen depletion likely contribute to the attenuated regenerative competence of the marrow and may reflect alterations in MSC phenotype. Here we summarize current concepts in bone marrow MSC identity, and within this context, review recent observations on changes in bone marrow population dynamics associated with aging and menopause.


Vaccine storage practices in pediatric offices.
Fifty pediatric offices and clinics in the metropolitan Los Angeles area were visited to assess vaccine storage practices. Questionnaires were administered to the personnel responsible for vaccine storage and the vaccine refrigerators were inspected. Only 16% of vaccine storage coordinators could cite appropriate storage temperatures for vaccines and 18% were unaware that heat can harm certain vaccines. Refrigerator thermometers were checked at least weekly in only 20% of offices, and 22% of the refrigerators had inappropriately high temperatures. Vaccines were routinely stored outside of the refrigerator uninsulated during the practice day in 16% of the offices visited. It is concluded that vaccine storage errors occur in pediatric offices at an unacceptably high frequency. Pediatricians should familiarize themselves with the guidelines for optimal vaccine storage in order to minimize the potential for vaccine failure in primary care practice.


Theoretical modeling of dendrite growth from conductive wire electro-polymerization.
Electropolymerization is a bottom-up materials engineering process of micro/nano-scale that utilizes electrical signals to deposit conducting dendrites morphologies by a redox reaction in the liquid phase. It resembles synaptogenesis in the brain, in which the electrical stimulation in the brain causes the formation of synapses from the cellular neural composites. The strategy has been recently explored for neuromorphic engineering by establishing link between the electrical signals and the dendrites' shapes. Since the geometry of these structures determines their electrochemical properties, understanding the mechanisms that regulate polymer assembly under electrically programmed conditions is an important aspect. In this manuscript, we simulate this phenomenon using mesoscale simulations, taking into account the important features of spatial-temporal potential mapping based on the time-varying signal, the motion of charged particles in the liquid due to the electric field, and the attachment of particles on the electrode. The study helps in visualizing the motion of the charged particles in different electrical conditions, which is not possible to probe experimentally. Consistent with the experiments, the higher AC frequency of electrical activities favors linear wire-like growth, while lower frequency leads to more dense and fractal dendrites' growth, and voltage offset leads to asymmetrical growth. We find that dendrites' shape and growth process systematically depend on particle concentration and random scattering. We discover that the different dendrites' architectures are associated with different Laplace and diffusion fields, which govern the monomers' trajectory and subsequent dendrites' growth. Such unconventional engineering routes could have a variety of applications from neuromorphic engineering to bottom-up computing strategies.


Cardiac sequelae of acute head injury.
An intensive 72 hour study of the cardiovascular effects of severe diffuse brain injury was made in seven patients. No other major injury was present. Patients received optimal care very rapidly after injury and intracranial pressure, which was continuously monitored, was maintained at or just above normal by elective positive pressure ventilation techniques. Three patients showed evidence of progressive myocardial ischaemia on continuous electrocardiographic monitoring. Two of these patients died. Ventricular arrhythmias were uncommon but one of the patients with ischaemia developed ventricular tachycardia. Heart rate patterns were very abnormal but did not predict complications. Blood pressure did not vary greatly and cardiac outputs were usually normal. Pronounced excesses of urinary catecholamines and serum creatine kinase 2 isoenzyme (CK MB) as well as total creatine kinase were found. Histological evidence of myocardial damage could be shown at necropsy in the one case whose heart was available for study. This study shows that the cardiac effects of isolated diffuse cerebral injury may be harmful and even fatal despite correction of secondary factors such as anoxia and raised intracranial pressure. The findings suggest that evaluation of the potential benefits of sympathetic blockade is warranted. Cardiac complications of cerebral damage deserve wider recognition by intensive care personnel, neurologists, and neurosurgeons.


Reinforced Labels: Multi-Agent Deep Reinforcement Learning for Point-Feature Label Placement.
Over the recent years, Reinforcement Learning combined with Deep Learning techniques has successfully proven to solve complex problems in various domains, including robotics, self-driving cars, and finance. In this paper, we are introducing Reinforcement Learning (RL) to label placement, a complex task in data visualization that seeks optimal positioning for labels to avoid overlap and ensure legibility. Our novel point-feature label placement method utilizes Multi-Agent Deep Reinforcement Learning to learn the label placement strategy, the first machine-learning-driven labeling method, in contrast to the existing hand-crafted algorithms designed by human experts. To facilitate RL learning, we developed an environment where an agent acts as a proxy for a label, a short textual annotation that augments visualization. Our results show that the strategy trained by our method significantly outperforms the random strategy of an untrained agent and the compared methods designed by human experts in terms of completeness (i.e., the number of placed labels). The trade-off is increased computation time, making the proposed method slower than the compared methods. Nevertheless, our method is ideal for scenarios where the labeling can be computed in advance, and completeness is essential, such as cartographic maps, technical drawings, and medical atlases. Additionally, we conducted a user study to assess the perceived performance. The outcomes revealed that the participants considered the proposed method to be significantly better than the other examined methods. This indicates that the improved completeness is not just reflected in the quantitative metrics but also in the subjective evaluation by the participants.


Efficacy and safety of key hole craniotomy for the evacuation of spontaneous cerebellar hemorrhage.
The efficacy and safety of cerebellar hemorrhage evacuation by key hole craniotomy and the importance of thorough evacuation and irrigation of the hematoma in the fourth ventricle to resolve obstructive hydrocephalus were assessed in 23 patients with spontaneous cerebellar hemorrhage (SCH) greater than 3 cm or with brainstem compression and hydrocephalus. A 5-cm elongated S-shaped scalp incision was made, and a 3-cm key hole craniotomy was performed over a cerebellar convexity area. The hematoma was immediately evacuated through a small corticotomy. The hematoma in the fourth ventricle was gently removed through the hematoma cavity, followed by thorough saline irrigation to release obstructive hydrocephalus. Patients classified retrospectively into favorable and poor outcome groups using the Glasgow Outcome Scale (GOS) scores of 4-5 vs. 1-3 showed significant differences with respect to the preoperative Glasgow Coma Scale, hematoma size and volume, and brainstem compression. Only 2 of the 23 patients required ventricular drainage and no postoperative complications were recorded. Patients treated by experienced and inexperienced surgeons showed no significant differences in the hematoma evacuation rate, postoperative GOS, and interval from skin incision to start of hematoma evacuation. Our simplified method of key hole craniotomy to treat SCH was less invasive but easy to perform, as even inexperienced neurosurgeons could obtain good surgical results. Thorough cleaning of the fourth ventricle minimized the necessity for ventricular drainage.


Predicting adolescent peer problems and antisocial activities: the relative roles of aggression and dysregulation.
This study examined the relative roles of aggression and other dysregulated behaviors in the prediction of adolescent peer problems and antisocial behavior. The social adjustment of 145 boys studied first in Grades 3-6 was assessed again 4 years later in Grades 7-10. At each time, peer ratings of aggressive, hyperactive-disruptive, withdrawn, and irritable-inattentive behaviors were collected. Aggression and withdrawal showed stability and were linked to peer difficulties in elementary school and in adolescence, but these behaviors indicated significant risk for adolescent rejection, victimization, and antisocial activity primarily when accompanied by irritable-inattentive behaviors. Results are discussed in terms of the potential role that difficulties regulating negative affect may play in the genesis of the particular constellation of irritable-inattentive behaviors studied here and the developmental significance of aggressive or withdrawn problem profiles that are or are not accompanied by these behavioral indicators of dysregulation.


Vasoactive intestinal polypeptide plays a key role in the microbial-neuroimmune control of intestinal motility.
Although chronic diarrhea and constipation are common, the treatment is symptomatic as their pathophysiology is poorly understood. Accumulating evidence suggests that the microbiota modulates gut function but the underlying mechanisms are unknown. We therefore investigated the pathways by which microbiota modulates gastrointestinal motility in different sections of the alimentary tract. Gastric emptying, intestinal transit, muscle contractility, acetylcholine release, gene expression and vasoactive intestinal polypeptide (VIP) immunoreactivity were assessed in wild-type and Myd88-/-Trif-/- mice in germ-free, gnotobiotic and SPF conditions. Effects of transient colonization and antimicrobials, as well as immune cell blockade were investigated. VIP levels were assessed in human full thickness biopsies by Western blot. Germ-free mice had similar gastric emptying but slower intestinal transit compared with SPF mice, or mice monocolonized with Lactobacillus rhamnosus or Escherichia coli, the latter having stronger effects. While muscle contractility was unaffected, its neural control was modulated by microbiota by upregulating jejunal VIP, which co-localized with and controlled cholinergic nerve function. This process was responsive to changes in the microbial composition and load, and mediated through TLR signaling, with enteric glia cells playing a key role. Jejunal VIP was lower in patients with chronic intestinal pseudo-obstruction compared with control subjects. Microbial control of gastrointestinal motility is both region- and bacteria-specific, it reacts to environmental changes, and is mediated by innate immunity-neural system interactions. Small intestinal VIP, by regulating cholinergic nerves, plays a key role in this process, thus providing a new therapeutic target for patients with motility disorders.


Disrupted mitochondrial function in the Opa3L122P mouse model for Costeff Syndrome impairs skeletal integrity.
Mitochondrial dysfunction connects metabolic disturbance with numerous pathologies, but the significance of mitochondrial activity in bone remains unclear. We have, therefore, characterized the skeletal phenotype in the Opa3L122P mouse model for Costeff syndrome, in which a missense mutation of the mitochondrial membrane protein, Opa3, impairs mitochondrial activity resulting in visual and metabolic dysfunction. Although widely expressed in the developing normal mouse head, Opa3 expression was restricted after E14.5 to the retina, brain, teeth and mandibular bone. Opa3 was also expressed in adult tibiae, including at the trabecular surfaces and in cortical osteocytes, epiphyseal chondrocytes, marrow adipocytes and mesenchymal stem cell rosettes. Opa3L122P mice displayed craniofacial abnormalities, including undergrowth of the lower mandible, accompanied in some individuals by cranial asymmetry and incisor malocclusion. Opa3L122P mice showed an 8-fold elevation in tibial marrow adiposity, due largely to increased adipogenesis. In addition, femoral length and cortical diameter and wall thickness were reduced, the weakening of the calcified tissue and the geometric component of strength reducing overall cortical strength in Opa3L122P mice by 65%. In lumbar vertebrae reduced vertebral body area and wall thickness were accompanied by a proportionate reduction in marrow adiposity. Although the total biomechanical strength of lumbar vertebrae was reduced by 35%, the strength of the calcified tissue (σmax) was proportionate to a 38% increase in trabecular number. Thus, mitochondrial function is important for the development and maintenance of skeletal integrity, impaired bone growth and strength, particularly in limb bones, representing a significant new feature of the Costeff syndrome phenotype.


Necrobiotic xanthogranuloma.
We reviewed 32 cases of necrobiotic xanthogranuloma and 16 cases from the world literature. Necrobiotic xanthogranuloma is a destructive dermal and subcutaneous xanthogranuloma that most frequently involves the face (periorbital region) and trunk. Monoclonal gammopathy is common (IgG-kappa in 23 cases and IgG-lambda in nine cases), and cryoglobulins have also been found. Low complement levels, anemia, and leukopenia are frequently present. Bone marrow examination shows plasma cell proliferation and, rarely, true myeloma. We describe mucosal, muscle, and systemic lesions, including xanthogranulomatous myocardial lesions. The clinical course is chronic and often progressive. Low-dose chlorambucil treatment is safe and effective, but individual patients have responded to treatment with corticosteroids, melphalan, local radiation, and plasma exchange.